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

Asymmetric synthesis method of (S)-chloroquine phosphate

A chloroquine phosphate, asymmetric technology, applied in the field of drug synthesis, can solve the problems of poor nucleophilic attack ability, low yield, unsatisfactory chiral selectivity of asymmetric catalysis, etc., and achieves few reaction steps and chiral selectivity. and high yield, suitable for large-scale industrial production

Pending Publication Date: 2021-01-26
江苏百奥信康医药科技有限公司
View PDF0 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The above synthetic method of asymmetric catalysis, although the synthetic route is very simple, because the amino group on the 4-amino-7-quinoline is an aromatic amine, the nucleophilic attack ability is relatively poor, so the yield of (S)-chloroquine that this method provides Efficiency is low (36.5%~68%), and the chiral selectivity of asymmetric catalysis is also not ideal, and the ee value of product (S)-chloroquine is 68%~92%

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
  • Asymmetric synthesis method of (S)-chloroquine phosphate
  • Asymmetric synthesis method of (S)-chloroquine phosphate
  • Asymmetric synthesis method of (S)-chloroquine phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Synthesis of (S, S)-5-(N'-diethylamino)-N-((1-phenyl)ethyl)-2-pentylamine

[0034] The reaction formula is as follows:

[0035]

[0036]Add methanol (150ml) into a 500mL hydrogenation reactor, start stirring, then add 5-diethylamino-2-pentanone (15.7g, 0.1mol), (S)-methylbenzylamine (12.7g, 0.105 mol) and isopropyl titanate (14.2g, 0.05mol). After stirring at room temperature for half an hour, wet Raney-Ni (25 g) was added, replaced with hydrogen three times, and hydrogen was introduced to 1.0 MPa, and the reaction was continued to stir at room temperature for 12 hours. After the reaction was over, the hydrogen in the kettle was released, the reaction kettle was opened, NaOH solution (1.0M, 100mL) was added, and stirring was continued at room temperature for 1 hour, and the reaction system became a suspension. After filtering, the filtrate evaporated about half of the solvent with a rotary evaporator, and then added dichloromethane for extraction three t...

Embodiment 2

[0037] Example 2: Synthesis of (S, S)-5-(N'-diethylamino)-N-((1-phenyl)ethyl)-2-pentylamine

[0038] The reaction formula is as follows:

[0039]

[0040] Add methanol (150ml) into a 500mL hydrogenation reactor, start stirring, then add 5-diethylamino-2-pentanone (15.7g, 0.1mol), (S)-methylbenzylamine (12.7g, 0.105 mol) and isopropyl titanate (28.4g, 0.1mol). After stirring at room temperature for half an hour, wet Raney-Ni (25 g) was added, replaced with hydrogen three times, and hydrogen was introduced to 1.0 MPa, and the reaction was continued to stir at room temperature for 12 hours. After the reaction was over, the hydrogen in the kettle was released, the reaction kettle was opened, NaOH solution (1.0M, 100mL) was added, and stirring was continued at room temperature for 1 hour, and the reaction system became a suspension. After filtering, the filtrate evaporated about half of the solvent with a rotary evaporator, and then added dichloromethane for extraction three t...

Embodiment 3

[0041] Example 3: Synthesis of (S, S)-5-(N'-diethylamino)-N-((1-phenyl)ethyl)-2-pentylamine

[0042] The reaction formula is as follows:

[0043]

[0044] Add methanol (150ml) into a 500mL hydrogenation reactor, start stirring, then add 5-diethylamino-2-pentanone (15.7g, 0.1mol), (S)-methylbenzylamine (12.7g, 0.105 mol) and isopropyl titanate (42.6g, 0.15mol). After stirring at room temperature for half an hour, wet Raney-Ni (25 g) was added, replaced with hydrogen three times, and hydrogen was introduced to 1.0 MPa, and the reaction was continued to stir at room temperature for 12 hours. After the reaction was over, the hydrogen in the kettle was released, the reaction kettle was opened, NaOH solution (1.0M, 100mL) was added, and stirring was continued at room temperature for 1 hour, and the reaction system became a suspension. After filtering, the filtrate evaporated about half of the solvent with a rotary evaporator, and then added dichloromethane for extraction three ...

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 a novel asymmetric synthesis method of (S) chloroquine. According to the invention, 5-(N-diethylamino)-2-pentanone and (S)-alpha-methyl benzylamine are adopted as raw materials,and in the presence of Lewis acid, an asymmetric reductive amination reaction is carried out to obtain (S,S)-5-(N'-diethylamino)-N-((1-phenyl)ethyl)-2-pentylamine, catalytic hydrogenation is performed to remove benzyl to obtain a side chain (S)-5-(N'-diethylamino)-2-amyl amine for synthesizing chloroquine, the (S)-5-(N'-diethylamino)-2-amyl amine is condensed with 4,7-dichloroquinoline to obtain(S)-chloroquine, salifying is performed with phosphoric acid, and recrystallizing is performed to obtain (S)-chloroquine phosphate with ee value of more than 99%, wherein the the total yield of the four-step reaction exceeds 70%; and the preparation method is stable, reliable, economical, efficient and easy to industrialize.

Description

technical field [0001] The invention relates to an asymmetric synthesis method of (S)-chloroquine phosphate, which belongs to the field of drug synthesis. Background technique [0002] The inventor has investigated the relevant data of chloroquine phosphate. Chloroquine is a traditional old medicine for the treatment of malaria, and it has also been used to treat autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. However, it has serious side effects in clinical use, especially the toxicity to the heart is fatal. . The content of the entry about chloroquine phosphate in Baidu Encyclopedia shows that the saturated carbon atom connected to the 4-position amino group of the quinoline ring in the chloroquine molecule should be a carbon atom with a chiral center, while the clinically used chloroquine phosphate is an exogenous racemate. In the training course for the high school Chemistry Olympiad that the inventor is currently studying, the teach...

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): C07D215/46
CPCC07D215/46C07B2200/07
Inventor 陈旭桓
Owner 江苏百奥信康医药科技有限公司
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