Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of raloxifene hydrochloride and intermediate thereof

A technology for raloxifene hydrochloride and an intermediate, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of difficult preparation of starting materials, unfavorable industrial production, and large environmental impact, and achieves the advantages of controlling impurities, improving atom utilization, Less side effects

Active Publication Date: 2020-05-12
江苏美迪克化学品有限公司
View PDF14 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] The reactions involved in the above method 7 and method 8 all need to use heavy metal catalysts, which not only has high cost but also has a great impact on the environment. At the same time, the starting materials are not easy to prepare, which is not conducive to 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 of raloxifene hydrochloride and intermediate thereof
  • Preparation method of raloxifene hydrochloride and intermediate thereof
  • Preparation method of raloxifene hydrochloride and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] A) Preparation of 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone (formula 3) :

[0065] (3-Methoxyphenyl) benzyl sulfide (50.0g, Formula 5) was dissolved in acetonitrile (700mL), cooled in an ice bath, and periodic acid (75.0g) and ferric chloride (1.1g, 6.8 mmol), reacted at 25°C for 6h, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with saline and 5% sodium thiosulfate solution successively, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, the obtained sulfide The crude sulfone compound (Formula 4) was mixed with 1-[2-(4-ethynylphenoxy)ethyl]piperidine (50.0g) and trifluoromethanesulfonic acid (163g, 1.09mol), and reacted at 70°C for 6h. After the reaction is completed, the reaction mixture is post-treated, and recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2- Benzylthio-4-methoxypheny...

Embodiment 2

[0073] A) Preparation of 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone (formula 3) :

[0074] (3-Methoxyphenyl) benzyl sulfide (65.0g, Formula 5) was dissolved in toluene (850mL), cooled in an ice bath, and periodic acid (170.0g) and ferric chloride (0.9g, 5.5 mmol), reacted at 27°C for 4h, evaporated to dryness under reduced pressure, extracted with dichloromethane, washed successively with brine and 5% sodium thiosulfate solution, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, the obtained sulfide The crude sulfone compound (Formula 4) was mixed with 1-[2-(4-ethynylphenoxy)ethyl]piperidine (43.0g) and trifluoromethanesulfonic acid (422g, 2.8mol), and reacted at 80°C for 4h. After the reaction is completed, the reaction mixture is post-treated, and recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2- Benzylthio-4-methoxyphenyl)etha...

Embodiment 3

[0082] A) Preparation of 1-{4-[2-(piperidin-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone (formula 3) :

[0083] (3-Methoxyphenyl) benzyl sulfide (300.0g, formula 5) was dissolved in methyl tert-butyl ether (4000mL), cooled in an ice bath, and periodic acid (700.0g, 3.07mol) and three Ferric chloride (5.0g, 0.03mol), reacted at 30°C for 2h, rotary evaporated to dryness under reduced pressure, extracted with dichloromethane, washed with saline and 5% sodium thiosulfate solution successively, dried over anhydrous sodium sulfate, and dried under reduced pressure Rotary evaporation to dryness, the obtained sulfoxide compound (formula 4) crude product was mixed with 1-[2-(4-ethynylphenoxy)ethyl]piperidine (230.0g), trifluoromethanesulfonic acid (1500.0g, 10mol ) mixed, reacted at 100°C for 2h, after the reaction was completed, the reaction mixture was post-treated, and recrystallized from a mixed solvent of ethyl acetate-petroleum ether to obtain 1-{4-[2-(piperidin-...

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 preparation method comprises the following steps: preparing a raloxifene hydrochloride precursor (intermediate 2) from 1-{4-[2-(piperidine-1-yl)ethyoxyl]phenyl}-2-(2-sulfydryl-4-methoxyphenyl)ethanone (intermediate 1) and 4-methoxybenzoyl halide, performing demethylation protection, and preparing raloxifene hydrochloride from the demethylated raloxifene hydrochloride precursor and hydrochloricacid. Herein, the intermediate 1 is generated by removing benzyl protection from an intermediate 3 (1-{4-[2-(piperidine-1-yl)ethoxy]phenyl}-2-(2-benzylthio-4-methoxyphenyl)ethanone) in trifluoroacetic acid through a reaction; (3-methoxyphenyl) benzyl sulfide is oxidized to generate a sulfoxide compound, and then the sulfoxide compound reacts with 1-[2-(4-ethynylphenoxy)ethyl]piperidine to generate an intermediate 3. The method has the advantages of mild reaction conditions, few side reactions, high yield, cheap reagent raw materials, easy recovery and easy preparation, and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of raloxifene hydrochloride and an intermediate thereof. Background technique [0002] Raloxifene hydrochloride (Raloxifene hydrochloride) is a selective estrogen receptor modulator first developed by Lilly Company in the United States. It was approved by the FDA in December 1997 and listed in the United States in January 1998. It is used for the prevention of postmenopausal women osteoporosis. The chemical name of raloxifene hydrochloride is [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl]{4-[2-(piperidin-1-yl)ethoxy ] phenyl} ketone hydrochloride, its chemical structural formula is: [0003] [0004] The preparation method of relevant raloxifene hydrochloride at present has the different processing methods of multiple documents and patent reports, each has its own characteristics and advantages and disadvantages. [000...

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): C07D333/56C07D295/088
CPCC07D295/088C07D333/56
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com