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

New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine

A key technology of methyl phenyl and tannamide, which is applied in the field of pharmaceutical synthesis and achieves the effects of easy availability of raw materials, mild reaction conditions and simple operation

Inactive Publication Date: 2015-11-18
CHENGDU XINJIE HIGH TECH DEV CO LTD
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of the large defects in the preparation methods of the key intermediates (compounds of formula III) reported in the literature, the industrialized production of netupitant and the reduction of production costs have been greatly affected; therefore, based on the huge impact of netupitant Market prospects, the design and development of a production process with mild reaction conditions, easy operation, low cost, and environment-friendly has become the focus of everyone's attention

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
  • New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine
  • New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine
  • New method for preparation of netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of N-methoxyformyl-6-(4-methyl-1-piperazinyl)-4-(2-methylphenyl)-3-pyridinamine (compound of formula II):

[0040] Add 70 g of 6-(4-methyl-1-piperazinyl)-4-(2-methylphenyl) nicotinamide into a one-necked flask, dissolve it with 1 L of anhydrous methanol, and then stir and cool down in an ice bath Finally, 80 g of iodobenzene diacetate and 26 g of potassium hydroxide were added, and the mixture was stirred and reacted in an ice bath for 1 hour. TLC monitored the completion of the reaction. After concentration, add 1L of water to the reaction liquid successively, extract 3 times with ethyl acetate, combine the organic layers, then wash twice with saturated sodium chloride solution, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate to obtain yellow Oil 65g. The yield is 85%. 1 H-NMR (CDCl 3 ,400MHz): δ =8.81(brs,1H),7.34~7.25(m,3H),7.12(d, J =8Hz),6.46(s,1H),5.92(s,1H),3.67(s,3H),3.55~3.54(m,4H),2.55(t, J =4Hz,4H),2.35(s,3H),2...

Embodiment 2

[0047] Preparation of N-methoxyformyl-6-(4-methyl-1-piperazinyl)-4-(2-methylphenyl)-3-pyridinamine (compound of formula II):

[0048] Under ice-bath conditions, 4g of iodobenzene diacetate was added in batches to 3g of 6-(4-methyl-1-piperazinyl)-4-(2-methylphenyl)nicotinamide and 4gCH 3 In the chloroform solution of ONa, after the addition was completed, the reaction was continued to be stirred and reacted for 3 h under an ice bath; the reaction was complete as monitored by TLC. Add 10 mL of water to the reaction solution to quench the reaction, extract 3 times with chloroform, combine the organic layers, then wash twice with saturated sodium chloride solution, dry the organic layer with anhydrous sodium sulfate, filter, and concentrate to give yellow oil 2.4 g, yield 62%.

[0049]

[0050] The solvent in this embodiment can also be replaced by other types of solvents, such as: acetone, N,N-dimethylformamide, dimethyl sulfoxide, methanol, and the like.

Embodiment 3

[0052] Preparation of N-methyl-6-(4-methyl-1-piperazinyl)-4-(2-methylphenyl)-3-pyridinamine (compound of formula III):

[0053] Dissolve 40 g of the compound of formula II in 1.5 L of toluene, place in an ice-water bath, and add dropwise 200 ml of red aluminum solution dissolved in 1 L of toluene. During the dropping process, the reaction is violent, and the temperature is kept below 50°C. After the dropwise addition was completed, the reaction was heated in an oil bath at 50° C., and the reaction was complete as monitored by TLC. The reaction solution was slowly added dropwise to 1N NaOH solution under ice bath, then ethyl acetate was added to extract the aqueous phase, and the organic layer was washed with saturated sodium chloride solution until neutral, dried with anhydrous sodium sulfate, filtered and concentrated to obtain brown yellow 30.5 g of oil, yield: 62%. 1 H-NMR (CDCl 3 ,400MHz): δ =7.74(s,1H),7.31~7.13(m,4H),6.47(s,1H),3.44~3.40(m,4H),2.77(s,3H),2.57(t, J =...

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

Belonging to the field of drug synthesis, the invention relates to a new method for preparation of the netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine. The method comprises the steps of: 1) in certain solvent, subjecting 6-(4-methyl-1-piperazinyl)-4-(2-methyl phenyl)nicotinamide (formula I compound) and ROX (X=H or Na) to Hoffman degradation reaction under the condition of iodobenzene diacetate or substituted Iodobenzene diacetate, thus obtaining a formula II compound; and 2) carrying out reduction reaction on the formula II compound to obtain N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine (formula III compound). The new method for preparation of the netupitant key intermediate N-methyl-4-(2-methyl phenyl)-6-(4-methyl-1-piperazinyl)-3-pyridylamine has the advantages of easily available production raw materials, mild reaction conditions and simple operation, avoids application of strong base and controlled reagents, and provides an environment-friendly generation process.

Description

technical field [0001] The invention relates to a new method for preparing N-methyl-4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinamine, a key intermediate of netupitant The method belongs to the field of drug synthesis. Background technique [0002] In October 2014, the U.S. Food and Drug Administration (FDA) approved Akynzeo (netupitant and palonosetron) for the treatment of nausea and vomiting in patients undergoing cancer chemotherapy. Among them, oral palonosetron was approved in 2008 for the prevention of nausea and vomiting in the acute phase after the initiation of cancer chemotherapy; netupitant is a new drug belonging to the serotonin receptor antagonist for the prevention of Nausea and vomiting in the acute and delayed phases of cancer chemotherapy. [0003] At present, there are few synthetic methods about netupitant, but a comprehensive analysis found that the synthetic methods reported in the literature all involve the synthesis of key intermediates ...

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): C07D213/74
CPCC07D213/74
Inventor 张善军关文捷程泷高红
Owner CHENGDU XINJIE HIGH TECH DEV CO LTD
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