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

Novel synthesis method of oseltamivir

A new synthesis and compound technology, applied in the field of drug synthesis, can solve the problems of unsatisfactory total yield and long steps

Active Publication Date: 2021-05-18
SHANDONG UNIV
View PDF4 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In 2018, Xu Hao's research group (J.Am.Chem.Soc.2018, 140, 10619-10626) realized the total synthesis of oseltamivir by using the iron-catalyzed olefin bis-azidation reaction as a key step, but this The route steps are long and require the use of azide compounds, and the overall yield is not ideal. The key steps of the reaction are described as the following synthetic route 5
[0016] At present, the economy and safety of the existing synthetic route of oseltamivir need to be further improved

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
  • Novel synthesis method of oseltamivir
  • Novel synthesis method of oseltamivir
  • Novel synthesis method of oseltamivir

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0094] The preparation method of hydrogen bond catalyst 1-((1R,2R)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (Ⅲ-1), comprising the steps of:

[0095] Add (1R,2R)-1,2-cyclohexanediamine (910.0 mg, 8.0 mmol) into 40 mL of anhydrous tetrahydrofuran, and then add 3,5-bis(tri Fluoromethyl)phenyl isothiocyanate (1.46mL, 8.0mmol), the dropwise addition time is 45 minutes; Silica gel column chromatography for purification, the eluent is a mixed solvent of dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is 100:1 to 20:1;

[0096] A white flaky solid product (2.81 g, yield 91%) was obtained as 1-((1R,2R)-2-aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)phenyl ) Thiourea (III-1). References: Liu, Y.; Kang, T.R.; Liu, Q.Z.; Chen, L.M.; Wang, Y.C.; Liu, J.; Xie, Y.M.; Yang, J.L.; -6093.

[0097] The reaction equation is as follows:

[0098]

preparation example 2

[0100] Hydrogen bond catalyst (R)-1-(2'-amino-[1,1'-binaphthyl]-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea ( Ⅲ-2) preparation method, comprising steps:

[0101] Under argon atmosphere, (R)-(+)-1,1'-bi-2-naphthylamine (610.0 mg, 2.16 mmol) was added to 9 mL of dry CH 2 Cl 2 3,5-bis(trifluoromethyl)phenyl isothiocyanate (329.0mg, 1.8mmol) was added dropwise to the above system under stirring at 0°C for 45 minutes; After that, it was raised to room temperature, and stirred and reacted at room temperature for 4 hours; after the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting product was purified by silica gel column chromatography, and the eluent was petroleum ether at a volume ratio: ethyl acetate=10:1 The solvents were mixed to obtain a light yellow solid product (590.0 mg, yield 63%), namely (R)-1-(2'-amino-[1,1'-binaphthyl]-2-yl)-3- (3,5-bis(trifluoromethyl)phenyl)thiourea (III-2). References: Galzerano, Patrizia; Benci...

preparation example 3

[0105] Hydrogen bond catalyst 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (Ⅲ-4) The preparation method comprises steps:

[0106] Add (1R,2R)-1,2-diphenylethylenediamine (910.0mg, 8.0mmol) into 10mL tetrahydrofuran, then add 3,5-bis(trifluoromethyl) dropwise under stirring at 0°C Phenyl isothiocyanate (1.46mL, 8.0mmol), the dropwise addition time was 45 minutes; after the dropwise addition, the reaction system was raised to room temperature, and the reaction was stirred at room temperature for 4h; the reaction liquid was distilled off the solvent under reduced pressure, and the obtained product Purify by silica gel column chromatography, the eluent is a mixed solvent of dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is 30:1 to 20:1, to obtain a white flaky solid (2.23g, harvested rate 83%), which is 1-((1R,2R)-2-amino-1,2-diphenylethyl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea ( III-4). References:...

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 synthesis method of oseltamivir. The synthesis method comprises the following steps: taking a compound (E)-2-(2-nitrovinyl) isoindoline-1,3-diketone and ethyl pyruvate as initial raw materials, and carrying out Michael addition reaction under the condition of catalysis of a thiourea catalyst to obtain a corresponding Michael addition product; then, subjecting the Michael addition product and (formyl methylene) triphenyl phosphine to a Wittig reaction and a Henry reaction in a pot so as to obtain a ring closing product; and forming an etherified product from the ring closing product and a trichloroacetonitrile intermediate, and performing reduction, acetylation and de-protection to obtain oseltamivir. The reaction route comprises six steps, raw materials used in each step of reaction are easy to obtain and not expensive, the operation is easy, the yield of each step of reaction is high, no heavy metal or azide is used in the whole synthesis process, and the method is green and safe and can be applied to industrial production.

Description

technical field [0001] The invention relates to a new synthesis method of oseltamivir, which belongs to the technical field of medicine synthesis. Background technique [0002] Oseltamivir is a neuraminidase inhibitor, which was synthesized for the first time in 1996. After being developed by Roche, it was launched in Switzerland in 1999 and launched in the Chinese market in 2002. It had certain drug activity in the fight against SARS in 2003. It soon became an important reserve drug for the World Health Organization and my country to prevent and control influenza. The molecular formula of oseltamivir is C 16 h 28 N 2 o 4 , the chemical name is: (3R,4R,5S)-4-acetamide-5-amino-3-(1-propoxyethyl ester)-1-cyclohexene-1-carboxylic acid ethyl ester, the structural formula is as follows Show. So far, oseltamivir (or oseltamivir phosphate, also known as Tamiflu or Tamiflu) is the world's most effective drug against avian influenza, so its synthesis and industrialization are ve...

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): C07C231/12C07C233/52
CPCC07C231/12C07D209/48C07C2601/16C07C233/52
Inventor 佟庆喆王瑶
Owner SHANDONG UNIV
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