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

3, 4-dihydropyrimidine benzonitrile derivative as well as preparation method and application thereof

A technology of dihydropyrimidine and benzonitrile, which is applied in the field of chemical medicine and can solve problems such as reducing the content

Inactive Publication Date: 2021-03-12
湖南千金湘江药业股份有限公司 +1
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no research report on this impurity, and it is urgent to conduct comprehensive and systematic research on this impurity in order to reduce its content in alogliptin benzoate medicines

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
  • 3, 4-dihydropyrimidine benzonitrile derivative as well as preparation method and application thereof
  • 3, 4-dihydropyrimidine benzonitrile derivative as well as preparation method and application thereof
  • 3, 4-dihydropyrimidine benzonitrile derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Embodiment 1 Preparation of compound of formula (1A): 2-((5-bromo-6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl ) methyl) benzonitrile

[0091] The synthetic route of formula (1A) compound sees image 3 . The specific method is as follows:

[0092] Put dichloroethane (45ml) and compound M1 (3.00, 10.9mmol) into a three-necked flask, add NBS (2.33g, 13.1mmol) and AIBN (0.09g, 0.5mmol) under stirring, turn on the heating, and the reaction solution Raise the temperature to 80°C for 3 hours, turn off the heating, and cool down to 20°C in an ice-water bath. Add 30ml of water to the reaction solution, stir and wash, collect the lower organic phase, and continue to wash with 15ml of 5% NaHCO 3 The solution was washed twice and once with 15 ml of saturated brine, and the lower organic phase was collected and dried by adding 3 g of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain off-white solid powder. ...

Embodiment 2

[0094] Example 2 Preparation of compound of formula (2A): 2-((5-bromo-6-methoxy-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H) -yl)methyl)benzonitrile

[0095] The synthetic route of formula (2A) compound sees Figure 4 . The specific method is as follows:

[0096] Add compound 1A (5g, 14.1mmol) and 40ml methanol into a three-necked flask, stir to dissolve and add K 2 CO 3 (3.90 g, 28.2 mmol). Turn on the heating, and keep the reaction at 65°C for 6h. The reaction solution was concentrated to dryness under reduced pressure, then 40ml of water and 30ml of dichloromethane were added, the organic phase was collected after stirring, the aqueous phase was extracted twice with 20ml of dichloromethane, the organic phases were combined, and dried by adding 5g of anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain an off-white solid powder, which was beaten with 20 ml MTBE at room temperature for 2 h. After filtra...

Embodiment 3

[0099] Example 3 Preparation of compound of formula (3A): (R)-2-((6-(3-aminopiperidin-1-yl)-5-bromo-3-methyl-2,4-dioxo- 3,4-Dihydropyrimidin-1(2H)-yl)methyl)benzonitrile

[0100] The synthetic route of formula (3A) compound sees Figure 5 . The specific method is as follows:

[0101] Put dichloroethane (45ml) and compound M2 (5.00, 14.7mmol) into a three-necked flask, add NBS (3.70g, 20.8mmol) and AIBN (0.09g, 0.7mmol) under stirring, turn on the heating, and the reaction solution Raise the temperature to 80°C for 4 hours, turn off the heating, and cool down to 20°C in an ice-water bath. Add 30ml of water to the reaction solution, stir and wash, collect the lower organic phase, and continue to wash with 15ml of 5% NaHCO 3 The solution was washed twice and once with 15 ml of saturated brine, and the lower organic phase was collected and dried by adding 3 g of anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain off-whit...

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

PropertyMeasurementUnit
wavelengthaaaaaaaaaa
Login to View More

Abstract

The invention provides a 3, 4-dihydropyrimidine benzonitrile derivative as well as a preparation method and application thereof. The invention discloses a structure of a specific impurity (RRT is an impurity of 1.22) generated in the process of preparing alogliptin benzoate by adopting the route of the original research patent for the first time. The series of impurities have a warning structure,and the content of the impurities in the alogliptin benzoate finished product needs to be detected according to related limits of the genetically toxic impurities. The invention further provides a preparation and purification method of the high-purity compound shown in the formula (A) and a detection method of the content of the impurity compound in the alogliptin benzoate medicine, and thereforequality control over the alogliptin benzoate medicine is achieved.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to a 3,4-dihydropyrimidinebenzonitrile derivative and a preparation method and application thereof. Background technique [0002] Alogliptin benzoate is a drug for treating type II diabetes based on the DPP-4 inhibitor mechanism. The synthetic route protected in the original research patent WO2007035629A2 ( figure 1 ), has the characteristics of cheap and easy-to-obtain raw materials, few reaction steps, simple post-treatment and high product purity. Therefore, this route is generally adopted by domestic industrialized large-scale production. [0003] Multiple batches of tests have found that during the preparation of compound 2a by this route, an impurity with RRT=1.22 will inevitably be produced, with a content between 0.8% and 1.2%. There is no research report on this impurity at present, and it is urgent to conduct comprehensive and systematic research on this impurity in ord...

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): C07D401/04G01N30/88G01N30/89
CPCC07D401/04G01N30/88G01N30/89G01N2030/8872
Inventor 宿亮龙承基侯岳华王洪峰周泽银殷作虎
Owner 湖南千金湘江药业股份有限公司
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